Ibuprofen (p-isobutylhydratropic acid) is a nonsteroidal composition that has long been recognized as being useful in the treatment of pain, inflammation, and fever. More particularly, ibuprofen has been found in clinical studies to be very effective in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis, the relief of mild to moderate pain, and the treatment of primary dysmenorrhea, among other things. Ibuprofen is at least as effective as other available high potency compounds, such as indomethacin and phenylbutazone, but without their attendant side effects, such as increased toxicity. Also, ibuprofen is obtainable over the counter in certain dosages, whereas other high potency compounds are not.
Dosages of ibuprofen have been available in the marketplace only in solid form such as in a tablet or a capsule form. There are significant segments of the population, however, which are unable to conveniently take medication in solid form. These include the pediatric population, the geriatric population, the infirm, and those who for whatever reason cannot or prefer not to swallow solid dosages of medication. For these people, the benefits of ibuprofen have been effectively unavailable because of the unavailability of liquid forms of the composition. Until this time, attempts to meet the needs of these people involved use of other analgesic compositions in liquid form such as liquid acetaminophen and liquid aspirin compositions. These efforts have been largely ineffective because the analgesia produced by these compositions is less than that obtainable with ibuprofen, acetaminophen compositions lack anti-inflammatory activity, and aspirin has come into disfavor because it causes gastrointestinal discomfort in some patients and it has been reported to be linked to Rye's syndrome in children.
In response to this long standing need, there have been many attempts to provide a liquid ibuprofen composition. For the most part, these attempts have been frustrated by the facts that ibuprofen is insoluble in water, has a very bitter taste, and is unstable in aqueous media.
Nicholson U.S. Pat. No. 3,385,886 refers to (1) a mixture of sodium 4-isobutylphenylacetate, orange peel infusion, and chloroform water, (2) a suspension of 4-isobutylphenylacetic acid and tragacanth powder in chloroform water, and (3) an elixir containing, among other things, sodium 4-cyclohexylphenylacetate, ethanol, and glycerol. These compositions all have limited shelf life, poor flavor, and substantial turbidity. Also, those compositions containing chloroform are unsuitable for administration to children and the elderly.
Mueller U.S. Pat. No. 4,447,451 refers to syrups, elixirs, and suspensions of ibuprofen. It says that water soluble forms of ibuprofen can be dissolved in an aqueous vehicle together with sugar, flavoring agents, and preservatives to form a syrup. It also says that an elixir may be prepared by using a hydroalcoholic vehicle, a sweetener, and a flavoring agent. It also says that a suspension may be prepared for insoluble forms of ibuprofen in a "suitable vehicle" with the aid of a suspending agent such as acacia, tragacanth, methylcellulose, and the like. No information is given regarding the nature of the "suitable vehicle". The patent completely fails to appreciate the problems of turbidity and stability that have to be addressed before a suitable liquid ibuprofen composition may be developed. In contrast to the invention of this application, the Mueller patent completely fails to appreciate how methylcellulose compositions are particularly useful in overcoming problems of prior liquid ibuprofen compositions and fails to teach any way of using methylcellulose compositions to overcome those problems. The Mueller patent's complete failure to suggest the invention of this application and its advantages is demonstrated by the specific recipe for an ibuprofen suspension given in the patent. That suspension is to be taken orally and gives a 100 mg. dose of ibuprofen per 5 ml. dose of suspension. It includes an aluminum salt of ibuprofen, citric acid, benzoic acid, sucrose, tragacanth, lemon oil, and deionized water. This composition is cloudy and not chemically stable for any length of time.
Arnold U.S. Pat. No. 4,571,400 refers to pharmaceutical compositions containing dihydrocodeine and ibuprofen. It says that those compositions may have every imaginable ingredient and physical characteristic. Specifically, those compositions, among other things, allegedly may be in liquid form, supposedly as solutions, suspensions, emulsions, syrups, elixirs, or pressurized compositions. The active ingredient allegedly can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. There is no indication of how any of this is to be accomplished. The liquid carrier may contain a host of different pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilisers, or osmoregulators. No idea is given about which of these ingredients are to be used, in what amounts they are to be used, or what characteristics would result if they were tried. Purported examples of liquid carriers for oral administration include water said to contain the additives listed above, for example, cellulose derivatives, preferably some unspecified sodium carboxymethylcellulose solution. Alcohols and their derivatives, and oils, are also said to be suitable liquid carriers. There is absolutely no recipe for preparing any liquid composition and Applicant is unaware of the existence of any such recipe apart from the invention of this application which may be used in conjunction with the wish list of the Arnold patent to prepare a liquid ibuprofen composition anything like that of this application. In the Examples, the Arnold patent only purports to describe how to prepare tablets and capsules, and not liquid compositions.
Arnold U.S. Pat. No. 4,587,252 refers to a pharmaceutical composition containing hydrocodone and ibuprofen. The patent purports to describe the entire spectrum of liquid compositions said to be possible for the compositions of the Arnold '400 patent and, like the Arnold '400 patent, gives no idea about how to achieve any of those liquid compositions or what one would get if one were to try to do so.
Moore et al. report a clinical trial using an aluminum ibuprofen suspension to relieve the pain of dental extractions in children (International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 23, No. 11-1985, pp. 573-577). No formulation for the suspension is given in the paper, although the paper does indicate that dosages of 200 mg. of ibuprofen were administered. A footnote indicates that the suspension was prepared by the assignee of the Mueller patent.
Haas U.S. Pat. No. 4,684,666 is not prior art, but it is referred to here to give some idea of the background of this invention. It refers to a stabilized liquid ibuprofen composition. Although the patent refers to a completely suitable ibuprofen composition in terms of taste, stability, and lack of turbidity, and in fact describes the first commercially acceptable liquid ibuprofen composition, Applicant has unexpectedly found that the clarity and stability of that ibuprofen composition can be improved upon with the invention of this application. In addition to improved clarity and stability, the invention of this application permits production of the ibuprofen composition with dramatically reduced labor costs in a process of markedly increased simplicity. This permits the marketing of a more palatable liquid ibuprofen composition of reduced cost particularly attractive for parents with small children, elderly people on fixed incomes, and sick persons burdened with high health care costs.